Women account for 65% of the approximately 1.5 million adults infected with HIV in Kenya. The majority of new HIV infections occur in women of child-bearing ages. As improved national antiretroviral therapy distribution programs and mother to child transmission interventions are implemented, the number of HIV exposed but uninfected (HIV EU) infants is expected to rise. These HIV EU infants have higher morbidity and mortality than non HIV exposed infants. The underlying mechanism is likely to be multifactorial with infant immunity playing a critical role. HIV+ pregnant women have elevated pro-inflammatory cytokines such as TNF-, but reduced IL-10 levels, indicative of dysregulated immune responses. The long term consequences of fetal exposure to maternal dysregulated chronic immune activation are not yet known, but several reports of HIV EU infants examined beyond the neonatal period show persistently activated T cell populations, higher levels of polyclonal antibodies, and increased B cell apoptosis compared to infants of HIV- mothers. Our central hypothesis is that prenatal exposure to the chronically activated maternal immune environment resulting from HIV infection modulates fetal immune development and the subsequent development of infant immunity to childhood vaccines among African infants. To test this hypothesis, we will examine the development of B cell immunity in Kenyan HIV EU infants compared to non HIV exposed infants. Specifically, we will examine infants from birth to 2 years of age focusing on characterizing B cell subsets by flow cytometry, evaluating the mechanisms by which HIV exposure modulates B cell memory responses, and quantifying B cell responses to infant vaccines. At a practical level, results of this research will inform local health care providers of the potential benefit of additional booster vaccines in this vulnerable population of HIV EU infants in Africa. The long term results will advance fundamental knowledge of how in utero exposure to HIV affects fetal/infant B cell ontogeny and responses to vaccines of public health importance in resource-limited countries. PUBLIC HEALTH RELEVANCE: Results of this study will advance our understanding of how in utero infection exposure, particularly HIV, affects fetal/infant B cell ontogeny and responses to vaccines of public health importance in resource-limited countries.